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  • Title: The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) functions as a dominant regulator of apoptosis in hippocampal neurons involving activation of the ERK survival pathway and upregulation of the antiapoptotic protein Bag-1.
    Author: Perkins D, Pereira EF, Aurelian L.
    Journal: J Virol; 2003 Jan; 77(2):1292-305. PubMed ID: 12502846.
    Abstract:
    Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) can trigger or block apoptosis in a cell type-dependent manner. We have recently shown that the protein kinase activity of the large subunit of the HSV-2 ribonucleotide reductase (R1) protein (ICP10 PK) blocks apoptosis in cultured hippocampal neurons by activating the extracellular signal-regulated kinase (ERK) survival pathway (Perkins et al., J. Virol. 76:1435-1449, 2002). The present studies were designed to better elucidate the mechanism of ICP10 PK-induced neuroprotection and determine whether HSV-1 has similar activity. The data indicate that apoptosis inhibition by ICP10 PK involves a c-Raf-1-dependent mechanism and induction of the antiapoptotic protein Bag-1 by the activated ERK survival pathway. Also associated with neuroprotection by ICP10 PK are increased activation/stability of the transcription factor CREB and stabilization of the antiapoptotic protein Bcl-2. HSV-1 and the ICP10 PK-deleted HSV-2 mutant ICP10DeltaPK activate JNK, c-Jun, and ATF-2, induce the proapoptotic protein BAD, and trigger apoptosis in hippocampal neurons. c-Jun activation and apoptosis are inhibited in hippocampal cultures infected with HSV-1 in the presence of the JNK inhibitor SP600125, suggesting that JNK/c-Jun activation is required for HSV-1-induced apoptosis. Ectopically delivered ICP10 PK (but not its PK-negative mutant p139) inhibits apoptosis triggered by HSV-1 or ICP10DeltaPK. Collectively, the data indicate that ICP10 PK-induced activation of the ERK survival pathway results in Bag-1 upregulation and overrides the proapoptotic JNK/c-Jun signal induced by other viral proteins.
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